Abstract 14771: Angiopoietin Like-2 (angptl2) Knock-Down Limits High-Fat Diet-Induced Fat Accumulation, Hypercholesterolemia and Prevents Endothelial Dysfunction in Mice
Obesity, characterized by fat accumulation, is associated with low-grade chronic inflammation that contributes to endothelial dysfunction. Angiopoietin like-2 (angptl2), an adipocyte-derived protein, is a pro-inflammatory mediator in obesity-related insulin resistance. However, its role in regulating endothelial function remains largely unknown. We hypothesized that lowering angptl2 levels limits high-fat diet (HFD)-induced endothelial dysfunction. An angptl2 knock-down (KD) mouse was generated to study the endothelial function in isolated and pressurized femoral arteries. In 3-month-old (mo) KD mice, endothelial function, as measured by acetylcholine (ACh)-induced vasodilatation, was better compared to that in age-matched wild-type (WT) mice (Emax=98±1, n=8 vs. 93±2 %, n=7; P<0.05; EC50=7.2±0.2, n=8 vs. 6.8±0.2, n=7; P=0.06). Nitric oxide (NO) was responsible for the sensitivity of ACh-mediated response in both strains, while prostacyclin contributed to maximal dilation in KD (P<0.05) but not in WT mice. Three-mo mice were then challenged by a 3-month HFD until 6 months of age. In fasting plasma, total cholesterol-to-HDL and LDL-to-HDL ratios increased significantly (P<0.05) only in WT but not in KD mice following HFD. HFD-fed KD mice showed less lipid droplet accumulation and significantly less triglyceride accumulation in the liver compared to WT (401±28, n=4 vs. 952±180 nmol/mg, n=5; P<0.01). In addition, average adipocyte diameter in epididymal white adipose tissue (eWAT) was significantly smaller in KD than in WT mice fed a HFD (86±7 vs. 108±3 μm, n=5; P<0.05). Pro-inflammatory gene markers TNFα and TGFβ mRNA rose ~2 folds (P<0.05) in eWAT of HFD-fed WT but not in KD mice. ACh-mediated vasorelaxation remained more sensitive in KD compared to WT mice fed a RD (EC50=7.0±0.1, n=13 vs. 6.7±0.1, n=10; P<0.05). When fed a HFD, both strains displayed similar total ACh-mediated responses; however, NO-dependent vasorelaxation was significantly blunted in WT after HFD (P<0.05), but was preserved in KD mice. We conclude that knock-down of angptl2 limits HFD-induced fat accumulation and hypercholesterolemia, and prevents endothelial dysfunction, specifically NO contribution to vasorelaxation.
- © 2013 by American Heart Association, Inc.